The prevalence of human papillomavirus (HPV)-associated oropharyngeal cancer (HPVOPC) is increasing in the USA (225% from 1988 to 2004). HPVOPC patients tend to be younger and have a favorable prognosis, with a 69% reduction in the risk of death compared with HPV-negative patients. However most HPVOPC patients present with advanced stage, and standard chemoradiation regimens can be associated with significant toxicity. Thus the patients who have a good prognosis are paradoxically at greater risk of therapy-related long-term poor quality-of-life outcomes. Immunotherapy has the potential to reduce toxicity through de-escalation of chemoradiation regimens, and potentially enhance long-term disease control.
The HR-HPV E6 and E7 proteins are consistently expressed in dysplasias and carcinomas, disrupting the cell cycle regulatory proteins p53 and pRb, respectively. The obligatory expression of E6 and E7 by both dysplastic and invasive malignant lesions, as well as the viral origin of these proteins, make them excellent targets for HPV therapeutic vaccines.
Listeria monocytogenes (Lm) is a food-borne gram-positive bacterium that can occasionally cause disease in humans, in particular elderly individuals, newborns, pregnant women and immunocompromised individuals. In addition to strongly activating innate immunity and inducing a cytokine response that enhances antigen-presenting cell (APC) function, Lm has the ability to replicate in the cytosol of APCs after escaping from the phagolysosome, mainly through the action of the listeriolysin O (LLO) protein. This unique intracellular life cycle allows antigens secreted by Lm to be processed and presented in the context of both MHC class I and II molecules, resulting in potent cytotoxic CD8+ and Th1 CD4+ T-cell-mediated immune responses.
The present invention addresses the issue of therapy-related long-term poor quality-of-life outcomes in patients having human papillomavirus (HPV)-associated oropharyngeal cancer by providing a composite therapy approach, which incorporates Listeria monocytogenes immunotherapy, thereby reducing toxicity through de-escalation of chemoradiation regimens, and potentially enhancing long-term disease control.